Compositions and methods for treating hair loss using c16-c20 aromatic tetrahydro prostaglandins

ABSTRACT

A method for treating hair loss in mammals uses compositions containing prostaglandin F analogs. The compositions can be applied topically to the skin. The compositions can arrest hair loss, reverse hair loss, and promote hair growth.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of and claims priority to U.S. patentapplication Ser. No. 11/565,297, filed on Nov. 30, 2006, which is adivisional of and claims priority to U.S. patent application Ser. No.09/774,555, filed on Jan. 31, 2001, which claims priority under 35U.S.C. § 119(e) to U.S. Provisional Application Ser. No. 60/193,846,filed on Mar. 31, 2000. This application claims priority to and fullyincorporates the subject matter of each of the applications mentionedabove.

FIELD OF THE INVENTION

This invention relates to compositions and methods for treating hairloss in mammals. More particularly, this invention relates tocompositions and methods for arresting or reversing hair loss, or both,and promoting hair growth.

BACKGROUND OF THE INVENTION

Hair loss is a common problem which is, for example, naturally occurringor chemically promoted through the use of certain therapeutic drugsdesigned to alleviate conditions such as cancer. Often such hair loss isaccompanied by lack of hair re-growth which causes partial or fullbaldness.

Hair growth on the scalp does not occur continuously, but rather occursby a cycle of activity involving alternating periods of growth and rest.This cycle is divided into three main stages; anagen, catagen, andtelogen. Anagen is the growth phase of the cycle and is characterized bypenetration of the hair follicle deep into the dermis with rapidproliferation of cells which are differentiating to form hair. The nextphase is catagen, which is a transitional stage marked by the cessationof cell division, and during which the hair follicle regresses throughthe dermis and hair growth ceases. The next phase, telogen, ischaracterized as the resting stage during which the regressed folliclecontains a germ with tightly packed dermal papilla cells. At telogen,the initiation of a new anagen phase is caused by rapid cellproliferation in the germ, expansion of the dermal papilla, andelaboration of basement membrane components. When hair growth ceases,most of the hair follicles reside in telogen and anagen is not engaged,thus causing the onset of full or partial baldness.

Attempts to invoke the re-growth of hair have been made by, for example,the promotion or prolongation of anagen. Currently, there are two drugsapproved by the United States Food and Drug Administration for thetreatment of male pattern baldness: topical minoxidil (marketed asROGAINE® by Pharmacia & Upjohn), and oral finasteride (marketed asPROPECIA® by Merck & Co., Inc.). However, the search for efficacioushair growth inducers is ongoing due to factors including safety concernsand limited efficacy.

The thyroid hormone thyroxine (“T4”) converts to thyronine (“T3”) inhuman skin by deiodinase I, a selenoprotein. Selenium deficiency causesa decrease in T3 levels due to a decrease in deiodinase I activity; thisreduction in T3 levels is strongly associated with hair loss. Consistentwith this observation, hair growth is a reported side effect ofadministration of T4. See, e.g., Berman, “Peripheral Effects ofL-Thyroxine on Hair Growth and Coloration in Cattle”, Journal ofEndocrinology, Vol. 20, pp. 282-292 (1960); and Gunaratnam, “The Effectsof Thyroxine on Hair Growth in the Dog”, J. Small Anim. Pract., Vol. 27,pp. 17-29 (1986). Furthermore, T3 and T4 have been the subject ofseveral patent publications relating to treatment of hair loss. See,e.g., Fischer et al., DE 1,617,477, published Jan. 8, 1970; Mortimer, GB2,138,286, published Oct. 24, 1984; and Lindenbaum, WO 96/25943,assigned to Life Medical Sciences, Inc., published Aug. 29, 1996.

Unfortunately, however, administration of T3 or T4, or both, to treathair loss is often not practicable because these thyroid hormones caninduce significant cardiotoxicity. See, e.g., Walker et al., U.S. Pat.No. 5,284,971, assigned to Syntex, issued Feb. 8, 1994 and Emmett etal., U.S. Pat. No. 5,061,798, assigned to Smith Kline & FrenchLaboratories, issued Oct. 29, 1991.

In an alternative approach, prostaglandins have been proposed to promotehair growth because prostaglandins may have a similar benefit to thyroidhormones, i.e., increasing hair length and changing pigmentation.Naturally occurring prostaglandins (e.g., PGA₂, PGB₂, PGE₁, PGF_(2α),and PGI₂) are C-20 unsaturated fatty acids. PGF_(2α), the naturallyoccurring Prostaglandin F analog in humans, is characterized by hydroxylgroups at the C9 and C11 positions on the alicyclic ring, a cis-doublebond between C5 and C6, and a trans-double bond between C13 and C14.PGF_(2α) has the formula:

Analogs of naturally occurring Prostaglandin F are known in the art. Forexample, see U.S. Pat. No. 4,024,179 issued to Bindra and Johnson on May17, 1977; German Patent No. DT-002,460,990 issued to Beck, Lerch,Seeger, and Teufel published on Jul. 1, 1976; U.S. Pat. No. 4,128,720issued to Hayashi, Kori, and Miyake on Dec. 5, 1978; U.S. Pat. No.4,011,262 issued to Hess, Johnson, Bindra, and Schaaf on Mar. 8, 1977;U.S. Pat. No. 3,776,938 issued to Bergstrom and Sjovall on Dec. 4, 1973;P. W. Collins and S. W. Djuric, “Synthesis of Therapeutically UsefulProstaglandin and Prostacyclin Analogs”, Chem. Rev., Vol. 93, pp.1533-1564 (1993); G. L. Bundy and F. H. Lincoln, “Synthesis of17-Phenyl-18,19,20-Trinorprostaglandins: I. The PG₁ Series”,Prostaglandin, Vol. 9 No. 1, pp. 1-4 (1975); W. Bartman, G. Beck, U.Lerch, H. Teufel, and B. Scholkens, “Luteolytic Prostaglandin: Synthesisand Biological Activity”, Prostaglandin, Vol. 17 No. 2, pp. 301-311(1979); C. Iiljebris, G. Selen, B. Resul, J. Sternschantz, and U.Hacksell, “Derivatives of 17-Phenyl-18, 19,20-trinorprostaglandin F₂α.Isopropyl Ester: Potential Antiglaucoma Agents”, Journal of MedicinalChemistry, Vol. 38, No. 2, pp. 289-304, (1995).

Prostaglandins in general have a wide range of biological activities.For example, PGE₂ has the following properties: a) regulator of cellproliferation, b) regulator of cytokine synthesis, c) regulator ofimmune responses and d) inducer of vasodilatation. Vasodilatation isthought to be one of the mechanisms of how minoxidil provides a hairgrowth benefit. In vitro results in the literature also indicate someanti-inflammatory properties of the prostaglandins. c.f.; Tanaka, H., BrJ. Pharm., 116, 2298, (1995).

However, previous attempts at using prostaglandins to promote hairgrowth have been unsuccessful. Different prostaglandin analogs can bindto multiple receptors at various concentrations with a biphasic effect.Furthermore, administration of naturally occurring prostaglandins cancause side effects such as inflammation, surface irritation, smoothmuscle contraction, pain, and bronchoconstriction. Therefore, it is anobject of this invention to provide methods for using prostaglandinanalogs to grow hair and to provide compositions that promote hairgrowth in humans and lower animals. It is a further object of thisinvention to provide a selection of appropriate prostaglandin analogsthat will promote hair growth and that do not cause significantundesirable side effects.

SUMMARY OF THE INVENTION

This invention relates to compositions and methods for treating hairloss. The methods comprise administering the compositions comprisingspecific prostaglandin F analogs that interact strongly withhair-selective receptors, such as the FP receptor. The choice ofprostaglandin F analog is important because it must selectively activatethe FP receptor and not activate any other receptors that would negatethe effect of activating the FP receptor. The compositions comprise:component A) the prostaglandin F analog, component B) a carrier, andoptionally component C) an activity enhancer.

Suitable prostaglandin F analogs (“PGF's”) for this invention have thegeneral formula:

wherein R¹ is preferably CO₂H or CO₂CH₃; R² is preferably H; R³ and R⁴are preferably H or CH₃; X is preferably OH; Y is selected from thegroup consisting of a divalent hydrocarbon group, O, S, S(O), S(O)₂, andNR¹¹, wherein R¹¹ is preferably a hydrogen atom or a methyl group; and Zis preferably thienyl or phenyl. Other suitable PGF's arepharmaceutically acceptable salts, hydrates, and biohydrolyzable amides,esters, and imides of the general formula above. Optical isomers,diastereomers, and enantiomers of the structure described above are alsosuitable for this invention. At all stereocenters where stereochemistryis not defined (i.e., C11, C12, C15, and C16), both epimers areenvisioned with the epimer that corresponds to the naturally-occurringone being preferred.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to compositions comprising prostaglandin Fanalogs (“PGF's”) to treat hair loss in mammals. “Treating hair loss”includes arresting hair loss or reversing hair loss, or both, andpromoting hair growth.

Publications and patents are referred to throughout this disclosure. AllU.S. patents cited herein are hereby incorporated by reference.

All percentages, ratios, and proportions used herein are by weightunless otherwise specified.

DEFINITION AND USAGE OF TERMS

The following is a list of definitions for terms, as used herein:

“Activate” means binding and signal transduction of a receptor.

“Acyl group” means a monovalent group suitable for acylating a nitrogenatom to form an amide or carbamate, an alcohol to form a carbonate, oran oxygen atom to form an ester group. Preferred acyl groups includebenzoyl, acetyl, tert-butyl acetyl, para-phenyl benzoyl, andtrifluoroacetyl. More preferred acyl groups include acetyl and benzoyl.The most preferred acyl group is acetyl.

“Aromatic group” means a monovalent group having a monocyclic ringstructure or fused bicyclic ring structure. Monocyclic aromatic groupscontain 5 to 10 carbon atoms, preferably 5 to 7 carbon atoms, and morepreferably 5 to 6 carbon atoms in the ring. Bicyclic aromatic groupscontain 8 to 12 carbon atoms, preferably 9 or 10 carbon atoms in thering. Aromatic groups are unsubstituted. The most preferred aromaticgroup is phenyl.

“Carbocyclic group” means a monovalent saturated or unsaturatedhydrocarbon ring. Carbocyclic groups are monocyclic, or are fused,spiro, or bridged bicyclic ring systems. Monocyclic carbocyclic groupscontain 4 to 10 carbon atoms, preferably 4 to 7 carbon atoms, and morepreferably 5 to 6 carbon atoms in the ring. Bicyclic carbocyclic groupscontain 8 to 12 carbon atoms, preferably 9 to 10 carbon atoms in thering. Carbocyclic groups are unsubstituted. Preferred carbocyclic groupsinclude cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, andcyclooctyl. More preferred carbocyclic groups include cyclohexyl,cycloheptyl, and cyclooctyl. The most preferred carbocyclic group iscycloheptyl. Carbocyclic groups are not aromatic.

“Cyano group” means a group containing a nitrile functionality.

“FP agonist” means a compound that activates the FP receptor.

“FP receptor” means known human FP receptors, their splice variants, andundescribed receptors that have similar binding and activation profilesas the known human FP receptors. “FP” means the receptor is of the classwhich has the highest affinity for PGF_(2α) of all the naturallyoccurring prostaglandins. FP refers to a known protein.

“Halogen atom” means F, Cl, Br, or I. Preferably, the halogen atom is F,Cl, or Br; more preferably Cl or F; and most preferably F.

“Halogenated heterogenous group” means a substituted heterogenous groupor a substituted heterocyclic group, wherein at least one substituent isa halogen atom. Halogenated heterogenous groups can have a straight,branched, or cyclic structure. Preferred halogenated heterogenous groupshave 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, and mostpreferably 1 to 3 carbon atoms. Preferred halogen atom substituents areCl and F.

“Halogenated hydrocarbon group” means a substituted monovalenthydrocarbon group or a substituted carbocyclic group, wherein at leastone substituent is a halogen atom. Halogenated hydrocarbon groups canhave a straight, branched, or cyclic structure. Preferred halogenatedhydrocarbon groups have 1 to 12 carbon atoms, more preferably 1 to 6carbon atoms, and most preferably 1 to 3 carbon atoms. Preferred halogenatom substituents are Cl and F. The most preferred halogenatedhydrocarbon group is trifluoromethyl.

“Heteroaromatic group” means an aromatic ring containing carbon and 1 to4 heteroatoms in the ring. Heteroaromatic groups are monocyclic or fusedbicyclic rings. Monocyclic heteroaromatic groups contain 5 to 10 memberatoms (i.e., carbon and heteroatoms), preferably 5 to 7, and morepreferably 5 to 6 in the ring. Bicyclic heteroaromatic rings contain 8to 12 member atoms, preferably 9 or 10 in the ring. Heteroaromaticgroups are unsubstituted. Preferred heteroaromatic groups includethienyl, thiazolyl, purinyl, pyrimidyl, pyridyl, and furanyl. Morepreferred heteroaromatic groups include thienyl, furanyl, and pyridyl.The most preferred heteroaromatic group is thienyl.

“Heteroatom” means an atom other than carbon in the ring of aheterocyclic group or the chain of a heterogeneous group. Preferably,heteroatoms are selected from the group consisting of nitrogen, sulfur,and oxygen atoms. Groups containing more than one heteroatom may containdifferent heteroatoms.

“Heterocyclic group” means a saturated or unsaturated ring structurecontaining carbon and 1 to 4 heteroatoms in the ring. No two heteroatomsare adjacent in the ring. Heterocyclic groups are not aromatic.Heterocyclic groups are monocyclic, or are fused or bridged bicyclicring systems. Monocyclic heterocyclic groups contain 4 to 10 memberatoms (i.e., including both carbon atoms and at least 1 heteroatom),preferably 4 to 7, and more preferably 5 to 6 in the ring. Bicyclicheterocyclic groups contain 8 to 12 member atoms, preferably 9 or 10 inthe ring. Heterocyclic groups are unsubstituted. Preferred heterocyclicgroups include piperzyl, morpholinyl, tetrahydrofuranyl,tetrahydropyranyl, and piperdyl.

“Heterogeneous group” means a saturated or unsaturated chain containing1 to 18 member atoms (i.e., including both carbon and at least oneheteroatom). No two heteroatoms are adjacent. Preferably, the chaincontains 1 to 12 member atoms, more preferably 1 to 6, and mostpreferably 1 to 4. The chain may be straight or branched. Preferredbranched heterogeneous groups have one or two branches, preferably onebranch. Preferred heterogeneous groups are saturated. Unsaturatedheterogeneous groups have one or more double bonds, one or more triplebonds, or both. Preferred unsaturated heterogeneous groups have one ortwo double bonds or one triple bond. More preferably, the unsaturatedheterogeneous group has one double bond. Heterogeneous groups areunsubstituted.

“Monovalent hydrocarbon group” means a chain of 1 to 18 carbon atoms,preferably 1 to 12 carbon atoms. “Lower monovalent hydrocarbon group”means a monovalent hydrocarbon group having 1 to 6, preferably 1 to 4carbon atoms. Monovalent hydrocarbon groups may have a straight chain orbranched chain structure. Preferred monovalent hydrocarbon groups haveone or two branches, preferably 1 branch. Preferred monovalenthydrocarbon groups are saturated. Unsaturated monovalent hydrocarbongroups have one or more double bonds, one or more triple bonds, orcombinations thereof. Preferred unsaturated monovalent hydrocarbongroups have one or two double bonds or one triple bond; more preferredunsaturated monovalent hydrocarbon groups have one double bond.

“Pharmaceutically acceptable” means suitable for use in a human or othermammal.

“PGF” means a prostaglandin F analog.

“Prostaglandin” means a fatty acid derivative which has a variety ofpotent biological activities of a hormonal or regulatory nature.

“Protecting group” is a group that replaces the active hydrogen of ahydroxyl moiety thus preventing undesired side reaction at the hydroxylmoiety. Use of protecting groups in organic synthesis is well known inthe art. Examples of protecting groups are found in Chapter 2 ProtectingGroups in Organic Synthesis by Greene, T. W. and Wuts, P. G. M., 2^(nd)ed., Wiley & Sons, Inc., 1991. Preferred protecting groups include silylethers, alkoxymethyl ethers, tetrahydropyranyl, tetrahydrofuranyl,esters, and substituted or unsubstituted benzyl ethers.

“Safe and effective amount” means a quantity of a prostaglandin highenough to provide a significant positive modification of the subject'scondition to be treated, but low enough to avoid serious side effects(at a reasonable benefit/risk ratio).

“Selective” means having a binding or activation preference for aspecific receptor over other receptors which can be quantitated basedupon receptor binding or activation assays.

“Subject” means a living, vertebrate, hair- or fur-bearing animal suchas a mammal (preferably human) in need of treatment.

“Substituted aromatic group” means an aromatic group wherein 1 to 4 ofthe hydrogen atoms bonded to carbon atoms in the ring have been replacedwith other substituents. Preferred substituents include: halogen atoms,cyano groups, monovalent hydrocarbon groups, substituted monovalenthydrocarbon groups, heterogeneous groups, aromatic groups, substitutedaromatic groups, or any combination thereof. More preferred substituentsinclude halogen atoms, monovalent hydrocarbon groups, and substitutedmonovalent hydrocarbon groups. Preferred substituted aromatic groupsinclude naphthyl. The substituents may be substituted at the ortho,meta, or para position on the ring, or any combination thereof. Thepreferred substitution pattern on the ring is ortho or meta. The mostpreferred substitution pattern is ortho.

“Substituted carbocyclic group” means a carbocyclic group wherein 1 to 4hydrogen atoms bonded to carbon atoms in the ring have been replacedwith other substituents. Preferred substituents include: halogen atoms,cyano groups, monovalent hydrocarbon groups, monovalent heterogeneousgroups, substituted monovalent hydrocarbon groups, aromatic groups,substituted aromatic groups, or any combination thereof. More preferredsubstituents include halogen atoms and substituted monovalenthydrocarbon groups. Carbocyclic group does not include aromatic rings.

“Substituted heteroaromatic group” means a heteroaromatic group wherein1 to 4 hydrogen atoms bonded to carbon atoms in the ring have beenreplaced with other substituents. Preferred substituents include:halogen atoms, cyano groups, monovalent hydrocarbon groups, substitutedmonovalent hydrocarbon groups, heterogeneous groups, substitutedheterogeneous groups, phenyl groups, phenoxy groups, or any combinationthereof. More preferred substituents include halogen atoms, halogenatedhydrocarbon groups, halogenated heterogenous groups, monovalenthydrocarbon groups, and phenyl groups.

“Substituted heterocyclic group” means a heterocyclic group wherein 1 to4 hydrogen atoms bonded to carbon atoms in the ring have been replacedwith other substituents. Preferred substituents include: halogen atoms,cyano groups, monovalent hydrocarbon groups, substituted monovalenthydrocarbon groups, heterogeneous groups, substituted heterogeneousgroups, halogenated hydrocarbon groups, halogenated heterogenous groups,phenyl groups, phenoxy groups, or any combination thereof. Morepreferred substituents include halogen atoms and halogenated hydrocarbongroups. Substituted heterocyclic groups are not aromatic.

“Substituted heterogeneous group” means a heterogeneous group, wherein 1to 4 of the hydrogen atoms bonded to carbon atoms in the chain have beenreplaced with other substituents. Preferred substituents include halogenatoms, hydroxy groups, alkoxy groups (e.g., methoxy, ethoxy, propoxy,butoxy, and pentoxy), aryloxy groups (e.g., phenoxy, chlorophenoxy,tolyloxy, methoxyphenoxy, benzyloxy, alkyloxycarbonylphenoxy, andacyloxyphenoxy), acyloxy groups (e.g., propionyloxy, benzoyloxy, andacetoxy), carbamoyloxy groups, carboxy groups, mercapto groups,alkylthio groups, acylthio groups, arylthio groups (e.g., phenylthio,chlorophenylthio, alkylphenylthio, alkoxyphenylthio, benzylthio, andalkyloxycarbonylphenylthio), aromatic groups (e.g., phenyl and tolyl),substituted aromatic groups (e.g., alkoxyphenyl, alkoxycarbonylphenyl,and halogenated phenyl), heterocyclic groups, heteroaromatic groups, andamino groups (e.g., amino, mono- and di-alkylamino having 1 to 3 carbonatoms, methylphenylamino, methylbenzylamino, alkanylamido groups of 1 to3 carbon atoms, carbamamido, ureido, and guanidino).

“Substituted monovalent hydrocarbon group” means a monovalenthydrocarbon group wherein 1 to 4 of the hydrogen atoms bonded to carbonatoms in the chain have been replaced with other substituents. Preferredsubstituents include halogen atoms; halogenated hydrocarbon groups;halogenated heterogneous groups; alkyl groups (e.g., methyl, ethyl,propyl, and butyl); hydroxy groups; alkoxy groups (e.g., methoxy,ethoxy, propoxy, butoxy, and pentoxy); aryloxy groups (e.g., phenoxy,chlorophenoxy, tolyloxy, methoxyphenoxy, benzyloxy,alkyloxycarbonylphenoxy, and acyloxyphenoxy); acyloxy groups (e.g.,propionyloxy, benzoyloxy, and acetoxy); carbamoyloxy groups; carboxygroups; mercapto groups; alkylthio groups; acylthio groups; arylthiogroups (e.g., phenylthio, chlorophenylthio, alkylphenylthio,alkoxyphenylthio, benzylthio, and alkyloxycarbonylphenylthio); aromarticgroups (e.g., phenyl and tolyl); substituted aromatic groups (e.g.,alkoxyphenyl, alkoxycarbonylphenyl, and halogenated phenyl);heterocyclic groups; heteroaryl groups; and amino groups (e.g., amino,mono- and di-alkanylamino groups of 1 to 3 carbon atoms,methylphenylamino, methylbenzylamino, alkanylamido groups of 1 to 3carbon atoms, carbamamido, ureido, and guanidino).

Prostaglandin F Analogs Used in the Invention

This invention relates to the use of prostaglandin F analogs (PGFs) totreat hair loss. “Treating hair loss” means arresting hair loss,reversing hair loss, or both, and promoting hair growth. Suitable PGFsfor use in this invention are selected from the group consisting of PGFshaving the structure:

and pharmaceutically acceptable salts, hydrates, and biohydrolyzableamides, esters, and imides thereof.

R¹ is selected from the group consisting of CO₂H, C(O)NHOH, CO₂R⁵,CH₂OH, S(O)₂R⁵, C(O)NHR⁵, C(O)NHS(O)₂R⁵, and tetrazole. R⁵ is selectedfrom the group consisting of monovalent hydrocarbon groups, substitutedmonovalent hydrocarbon groups, aromatic groups, substituted aromaticgroups, carbocyclic groups, substituted carbocyclic groups,heterogeneous groups, substituted heterogeneous groups, heterocyclicgroups, substituted heterocyclic groups, heteroaromatic groups, andsubstituted heteroaromatic groups. Preferably, R⁵ is selected from thegroup consisting of CH₃, C₂H₅, and C₃H₇. Preferably, R¹ is selected fromthe group consisting of CO₂H, CO₂CH₃, CO₂C₂H₅, CO₂C₃H₇, CO₂C₄H₉,CO₂C₃H₇O₂, and C(O)NHS(O)₂R⁵. More preferably, R¹ is selected from thegroup consisting of CO₂H, CO₂CH₃, CO₂C₂H₅, and CO₂C₃H₇. Most preferably,R¹ is selected from the group consisting of CO₂H, CO₂CH₃, and CO₂C₃H₇.

R² is a hydrogen atom or a lower monovalent hydrocarbon group. R² ispreferably a hydrogen atom or a methyl group.

R³ and R⁴ are each independently selected from the group consisting ofH, CH₃, C₂H₅, OR¹⁰, SR¹⁰, and OH; with the proviso that both R³ and R⁴are not OH. R¹⁰ is selected from the group consisting of a monovalenthydrocarbon group, a substituted monovalent hydrocarbon group, aheterogeneous group, a substituted heterogeneous group, a carbocyclicgroup, a substituted carbocyclic group, an aromatic group, a substitutedaromatic group, a heteroaromatic group, and a substituted heteroaromaticgroup; with the proviso that R¹⁰ has 1 to 8 member atoms. Preferably, R³and R⁴ are both hydrogen atoms.

X is selected from the group consisting of NR⁶R⁷, OR⁸, SR⁹, S(O)R⁹, andS(O)₂R⁹. Preferably, X is selected from the group consisting of NR⁶R⁷and OR⁸. More preferably, X is OH.

R⁶, R⁷, and R⁸ are each independently selected from the group consistingof hydrogen atoms, acyl groups, monovalent hydrocarbon groups,substituted monovalent hydrocarbon groups, heterogeneous groups,substituted heterogeneous groups, carbocyclic groups, substitutedcarbocyclic groups, aromatic groups, substituted aromatic groups,heteroaromatic groups, and substituted heteroaromatic groups.Preferably, R⁶ and R⁷ are selected from the group consisting of H, CH₃,and C₂H₅. Preferably, R⁸ is selected from the group consisting of H,CH₃, C₂H₅, and C₃H₇.

R⁹ is selected from the group consisting of monovalent hydrocarbongroups, substituted monovalent hydrocarbon groups, heterogeneous groups,substituted heterogeneous groups, carbocyclic groups, substitutedcarbocyclic groups, heterocyclic groups, substituted heterocyclicgroups, aromatic groups, substituted aromatic groups, heteroaromaticgroups, and substituted heteroaromatic groups. Preferably, R⁹ isselected from the group consisting of CH₃, and C₂H₅.

Y is selected from the group consisting of an oxygen atom, a divalenthydrocarbon group, a sulfur-containing moiety, and a nitrogen-containinggroup. The divalent hydrocarbon group has the formula (CH₂)_(n), whereinn is an integer with a value of 0 to 3. Preferably, n is 0, 1, or 2;more preferably, n is 1.

The sulfur-containing moiety for Y is selected from the group consistingof a sulfur atom, S(O), and S(O)₂. When Y is a sulfur-containing moiety,it preferably is a sulfur atom.

The nitrogen-containing group for Y has the formula NR¹¹. R¹¹ isselected from the group consisting of a hydrogen atom, an acyl group, amonovalent hydrocarbon group, a substituted monovalent hydrocarbongroup, a heterogeneous group, a substituted heterogeneous group, acarbocyclic group, a substituted carbocyclic group, a heterocyclicgroup, a substituted heterocyclic group, an aromatic group, asubstituted aromatic group, a heteroaromatic group, and a substitutedheteroaromatic group. Preferably R¹¹ is H or CH₃.

Z is selected from the group consisting of a carbocyclic group, asubstituted carbocyclic group, a heterocyclic group, a substitutedheterocyclic group, an aromatic group, a substituted aromatic group, aheteroaromatic group, and a substituted heteroaromatic group. PreferablyZ is selected from the group consisting of a monocyclic carbocyclicgroup, a substituted monocyclic carbocyclic group, a monocyclicheterocyclic group, a substituted monocyclic heterocyclic group, amonocyclic aromatic group, a substituted monocyclic aromatic group, amonocyclic heteroaromatic group, and a substituted monocyclicheteroaromatic group. More preferably, Z is selected from the groupconsisting of a monocyclic aromatic group, a substituted monocyclicaromatic group, a monocyclic heteroaromatic group, and a substitutedmonocyclic heteroaromatic group. Most preferably, Z is thienyl orphenyl.

Optical isomers, diastereomers, and enantiomers of the structuredescribed above are also suitable for use in this invention. At allstereocenters where stereochemistry is not defined (i.e., C11, C12, C15,and C16), both epimers are envisioned.

Examples of suitable PGF's having the formula above wherein Y isselected from the group consisting of NR¹¹, S, S(O), and S(O)₂ include:

-   13,14-dihydro-16-(3-methylphenylthio)-16-tetranor Prostaglandin F₁α    methyl ester;-   13,14-dihydro-16-(3-methylphenylthio)-16-tetranor Prostaglandin F₁α;-   3,14-dihydro-16-(3-fluorophenylthio)-16-tetranor Prostaglandin F₁α;-   13,14-dihydro-16-(3-fluorophenylthio)-16-tetranor Prostaglandin F₁α    methyl ester;-   13,14-dihydro-16-(3-fluorophenylthio)-16-tetranor Prostaglandin F₁α    isopropyl ester;-   13,14-dihydro-16-(2,6-difluorophenylthio)-16-tetranor Prostaglandin    F₁α methyl ester;-   13,14-dihydro-16-(3,5-difluorophenylthio)-16-tetranor Prostaglandin    F₁α;-   13,14-dihydro-16-(2-methylphenylthio)-16-tetranor Prostaglandin F₁α    methyl ester;-   13,14-dihydro-16-(4-methylphenylthio)-16-tetranor Prostaglandin F₁α    methyl ester;-   13,14-dihydro-16-(4-methylphenylthio)-16-tetranor Prostaglandin F₁α;-   13,14-dihydro-16-(2-fluorophenylthio)-16-tetranor Prostaglandin F₁α    methyl ester;-   13,14-dihydro-16-(2-fluorophenylthio)-16-tetranor Prostaglandin F₁α;-   13,14-dihydro-15-methyl-16-(3-fluorophenylthio)-16-tetranor    Prostaglandin F₁α methyl ester;-   13,14-dihydro-15-methyl-16-(3-fluorophenylthio)-16-tetranor    Prostaglandin F₁α;-   13,14-dihydro-15-methyl-16-(2-methylphenylthio)-16-tetranor    Prostaglandin F₁α methyl ester;-   13,14-dihydro-15-methyl-16-(2-methylphenylthio)-16-tetranor    Prostaglandin F₁α;-   13,14-dihydro-16-(3-fluorophenylsulfonyl)-16-tetranor Prostaglandin    F₁α;-   13,14-dihydro-16-(3-methylphenylamino)-16-tetranor prostaglandin F₁α    methyl ester;-   13,14-dihydro-16-(3-methylphenylamino)-16-tetranor prostaglandin    F₁α;-   13,14-dihydro-16-(2-methylphenylamino)-16-tetranor prostaglandin F₁α    methyl ester;-   13,14-dihydro-16-(2-methylphenylamino)-16-tetranor prostaglandin    F₁α;-   13,14-dihydro-16-(2-fluorophenylthio)-16-tetranor prostaglandin    F₁α1-hydroxamic acid;-   13,14-dihydro-16-(3-chlorophenylamino)-16-tetranor prostaglandin F₁α    1-hydroxamic acid;-   13,14-dihydro-16-(3-trifluoromethylphenylthio)-16-tetranor    Prostaglandin F₁α methyl ester;-   13,14-dihydro-16-(3-trifluoromethylphenylthio)-16-tetranor    Prostaglandin F₁α;-   13,14-dihydro-16-(3-trifluoromethylphenylthio)-16-tetranor    prostaglandin F₁α 1-hydroxamic acid;-   13,14-dihydro-16-(phenylthio)-16-tetranor Prostaglandin F₁α methyl    ester;-   13,14-dihydro-16-(phenylthio)-16-tetranor Prostaglandin F₁α    isopropyl ester;-   13,14-dihydro-15-methyl-16-(phenylthio)-16-tetranor Prostaglandin    F₁α methyl ester;-   13,14-dihydro-15-methyl-16-(phenylthio)-16-tetranor Prostaglandin    F₁α;-   13,14-dihydro-16-(phenylamino)-16-tetranor prostaglandin F₁αmethyl    ester;-   13,14-dihydro-16-(phenylamino)-16-tetranor prostaglandin F₁α;-   13,14-dihydro-16-(2-thienylthio)-16-tetranor prostaglandin F₁α    methyl ester;-   13,14-dihydro-16-(2-thienylthio)-16-tetranor prostaglandin F₁α;-   13,14-dihydro-16-(1-napthylthio)-16-tetranor Prostaglandin F₁α    isopropyl ester;-   13,14-dihydro-16-(1-napthylthio)-16-tetranor Prostaglandin F₁α; and-   13,14-dihydro-15-butoxy-15-dehydroxy-16-(phenylthio)-16-tetranor    prostaglandin F₁α methyl ester.

Examples of suitable PGF's having the formula above wherein Y is adivalent hydrocarbon group include:

-   13,14-dihydro-17-(2,4-difluorophenyl)-17-trinor prostaglandin F₁α    methyl ester;-   13,14-dihydro-17-(2,4-difluorophenyl)-17-trinor prostaglandin F₁α;-   13,14-dihydro-17-(2-fluorophenyl)-17-trinor prostaglandin F₁α methyl    ester;-   13,14-dihydro-17-(2-fluorophenyl)-17-trinor prostaglandin F₁α;-   13,14-dihydro-17-(3-fluorophenyl)-17-trinor prostaglandin F₁α methyl    ester;-   13,14-dihydro-17-(3-fluorophenyl)-17-trinor prostaglandin F₁α;-   13,14-dihydro-17-(4-fluorophenyl)-17-trinor prostaglandin F₁α methyl    ester;-   13,14-dihydro-17-(4-fluorophenyl)-17-trinor prostaglandin F₁α;-   13,14-dihydro-17-(2-methoxyphenyl)-17-trinor prostaglandin F₁α    methyl ester;-   13,14-dihydro-17-(2-methoxyphenyl)-17-trinor prostaglandin F₁α;-   13,14-dihydro-17-(3-methoxyphenyl)-17-trinor prostaglandin F₁α    methyl ester;-   13,14-dihydro-17-(3-methoxyphenyl)-17-trinor prostaglandin F₁α;-   13,14-dihydro-17-(4-methoxyphenyl)-17-trinor prostaglandin F₁α    methyl ester;-   13,14-dihydro-17-(4-methoxyphenyl)-17-trinor prostaglandin F₁α;-   13,14-dihydro-17-(3,5-difluorophenyl)-17-trinor prostaglandin F₁α    isopropyl ester;-   13,14-dihydro-18-(2-thienyl)-18-dinor prostaglandin F₁α methyl    ester;-   13,14-dihydro-18-(2-thienyl)-18-dinor prostaglandin F₁α isopropyl    ester;-   13,14-dihydro-17-((2-trifluoromethyl)phenyl)-17-trinor prostaglandin    F₁α methyl ester;-   13,14-dihydro-17-((2-trifluoromethyl)phenyl)-17-trinor prostaglandin    F₁α;-   13,14-dihydro-17-((3-trifluoromethyl)phenyl)-17-trinor prostaglandin    F₁α methyl ester;-   13,14-dihydro-17-((3-trifluoromethyl)phenyl)-17-trinor prostaglandin    F₁α;-   13,14-dihydro-17-((4-trifluoromethyl)phenyl)-17-trinor prostaglandin    F₁α methyl ester;-   13,14-dihydro-17-((4-trifluoromethyl)phenyl)-17-trinor prostaglandin    F₁α;-   13,14-dihydro-17-(2-methylphenyl)-17-trinor prostaglandin F₁α methyl    ester;-   13,14-dihydro-17-(2-methylphenyl)-17-trinor prostaglandin F₁α;-   13,14-dihydro-17-(3-methylphenyl)-17-trinor prostaglandin F₁α methyl    ester;-   13,14-dihydro-17-(3-methylphenyl)-17-trinor prostaglandin F₁α;-   13,14-dihydro-17-(4-methylphenyl)-17-trinor prostaglandin F₁α methyl    ester; and-   13,14-dihydro-17-(4-methylphenyl)-17-trinor prostaglandin F₁α.

Examples of suitable PGF's having the formula above wherein Y is anoxygen atom include:

-   13,14-dihydro-16,16-dimethyl-16-(2-fluorophenoxy)-16-tetranor    prostaglandin F₁α;-   13,14-dihydro-16,16-dimethyl-16-(2-methylphenoxy)-16-tetranor    Prostaglandin F₁α;-   13,14-dihydro-16,16-dimethyl-16-(2,3 difluorophenoxy)-16-tetranor    Prostaglandin F₁α;-   13,14-dihydro-16-(2,5 difluorophenoxy)-16-tetranor Prostaglandin    F₁α;-   13,14-dihydro-16-(3-fluoro-5-trifluoromethyl phenoxy)-16-tetranor    Prostaglandin F₁α isopropyl ester;-   13,14-dihydro-16,16-dimethyl-16-(4-chlorophenoxy)-16-tetranor    Prostaglandin F₁α;-   13,14-dihydro-16-methyl-16-(3-chlorophenoxy)-16-tetranor    Prostaglandin F₁α isopropyl ester;-   13,14-dihydro-16-isopropyl-16-(2-fluorophenoxy)-16-tetranor    prostaglandin F₁α;-   13,14-dihydro-16-ethyl-16-(2-methylphenoxy)-16-tetranor    Prostaglandin F₁α isopropyl ester;-   13,14-dihydro-16-(hydroxymethyl)-16-phenoxy-16-tetranor    Prostaglandin F₁α;-   13,14-dihydro-16-methyl-16-(4-ethylphenoxy)-16-tetranor    Prostaglandin F₁α;-   13,14-dihydro-16-methyl-16-(3-chlorophenoxy)-16-tetranor    Prostaglandin F₁α methyl ester;-   13,14-dihydro-16-methyl-16-(4-phenylphenoxy)-16-tetranor    Prostaglandin F₁α isopropyl ester;-   13,14-dihydro-16,16-dimethyl-16-(4-phenoxyphenoxy)-16-tetranor    Prostaglandin F₁α isopropyl ester;-   13,14-dihydro-16,16-dimethyl-16-(2-fluorophenoxy)-16-tetranor    Prostaglandin F₁α hydroxamic acid;-   13,14-dihydro-16-methyl-16-(3-chlorophenoxy)-16-tetranor    Prostaglandin F₁α 1-hydroxamic acid;-   13,14-dihydro-16-methoxymethyl-16-(2,3-difluorophenoxy)-16-tetranor    Prostaglandin F₁α 1-hydroxamic acid;-   13,14-dihydro-16-phenoxy-16-tetranor Prostaglandin F₁α    methanesulfonamide;-   13,14-dihydro-15-fluoro-16-(2-fluorophenoxy)-16-tetranor    Prostaglandin F₁α methyl ester;-   13,14-dihydro-15-methyl-16,16-dimethyl-16-(2-fluorophenoxy)-16-tetranor    Prostaglandin F₁α;-   13,14-dihydro-15-fluoro-16-(2,3-difluorophenoxy)-16-tetranor    Prostaglandin F₁α-hydroxamic acid;-   13,14-dihydro-15-methylthio-15-dehydroxy-16-(2-methylphenoxy)-16-tetranor    Prostaglandin F₁α;-   13,14-dihydro-15-methylthio-15-dehydroxy-16-methyl-16-(2-methylphenoxy)-16-tetranor    Prostaglandin F₁α 1-hydroxamic acid;-   13,14-dihydro-15-methoxy-16,16-dimethyl-16-(2-fluorophenoxy)-16-tetranor    Prostaglandin F₁α 1-hydroxamic acid;-   13,14-dihydro-15-ethoxy-15-dehydroxy-16-phenoxy-16-tetranor    Prostaglandin F₁α isopropyl ester;-   13,14-dihydro-15-sulfonylmethyl-15-dehydroxy-16-methyl-16-(2-methylphenoxy)-16-tetranor    Prostaglandin F₁α methyl ester;-   13,14-dihydro-15-sulfoxylmethyl-15-dehydroxy-16-methyl-16-(2-methylphenoxy)-16-tetranor    Prostaglandin F₁α methyl ester;-   13,14-dihydro-15-methyl-15-methylamino-15-dehydroxy-16,16-dimethyl-16-(2-fluorophenoxy)-16-tetranor    Prostaglandin F₁α methyl ester;-   13,14-dihydro-15-methyl-15-methylamino-15-dehydroxy-16-methyl-16-(2-methylphenoxy)-16-tetranor    Prostaglandin F₁α 1-hydroxamic acid;-   13,14-dihydro-15-methyl-15-(N,N-dimethylamino)-16-ethyl-16-(2-fluorophenoxy)-16-tetranor    Prostaglandin F₁α isopropyl ester; and-   13,14-dihydro-16(2,6-difluorophenoxy)-16-tetranor Prostaglandin F₁α    glyceryl ester.

Suitable PGF's are known in the art. Examples of suitable PGF's andmethods for their preparation are disclosed in International PublishedPatent Application Numbers WO 99/12895A1, WO 99/12896A1, and WO99/12899A1, and in U.S. Pat. No. 5,977,173.

COMPOSITIONS OF THE INVENTION

This invention further relates to a composition for treating hair loss.The composition comprises A) the PGF described above and B) a carrier.The composition may further comprise C) one or more optional activityenhancers. The composition can be a pharmaceutical or cosmeticcomposition, administered for treatment or prophylaxis of hair loss.Standard pharmaceutical formulation techniques are used, such as thosedisclosed in Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa. (1990).

The composition further comprises component B) a carrier. “Carrier”means one or more compatible substances that are suitable foradministration to a mammal. Carrier includes solid or liquid diluents,hydrotopes, surface-active agents, and encapsulating substances.“Compatible” means that the components of the composition are capable ofbeing comingled with the PGF'S, and with each other, in a manner suchthat there is no interaction which would substantially reduce theefficacy of the composition under ordinary use situations. Carriers mustbe of sufficiently high purity and sufficiently low toxicity to renderthem suitable for administration to the mammal being treated. Thecarrier can be inert, or it can possess pharmaceutical benefits,cosmetic benefits, or both.

The choice of carrier for component B) depends on the route by which A)the PGF will be administered and the form of the composition. Thecomposition may be in a variety of forms, suitable, for example, forsystemic administration (e.g., oral, rectal, nasal, sublingual, buccal,or parenteral) or topical administration directly to the locus ofdesired hair growth (e.g., local application on the skin, ocular,liposome delivery systems, or iontophoresis). Topical administration ispreferred.

Carriers for systemic administration typically comprise one or moreingredients selected from the group consisting of a) diluents, b)lubricants, c) binders, d) disintegrants, e) colorants, f) flavors, g)sweeteners, h) antioxidants, j) preservatives, k) glidants, m) solvents,n) suspending agents, o) surfactants, combinations thereof, and others.

Ingredient a) is a diluent. Suitable diluents include sugars such asglucose, lactose, dextrose, and sucrose; polyols such as propyleneglycol; calcium carbonate; sodium carbonate; glycerin; mannitol; andsorbitol.

Ingredient b) is a lubricant. Suitable lubricants are exemplified bysolid lubricants including silica, talc, stearic acid and its magnesiumsalts and calcium salts, calcium sulfate; and liquid lubricants such aspolyethylene glycol and vegetable oils such as peanut oil, cottonseedoil, sesame oil, olive oil, corn oil and oil of theobroma.

Ingredient c) is a binder. Suitable binders includepolyvinylpyrrolidone; magnesium aluminum silicate; starches such as cornstarch and potato starch; gelatin; tragacanth; and cellulose and itsderivatives, such as ethyl cellulose, methylcellulose,hydroxypropylmethylcellulose, microcrystalline cellulose, and sodiumcarboxymethylcellulose; carbomer; providone; acacia; guar gum; andxanthan gum.

Ingredient d) is a disintegrant. Suitable disintegrants include agar,alginic acid and the sodium salt thereof, effervescent mixtures,croscarmelose, crospovidone, sodium carboxymethyl starch, sodium starchglycolate, clays, and ion exchange resins.

Ingredient e) is a colorant such as an FD&C dye.

Ingredient f) is a flavor such as menthol, peppermint, and fruitflavors.

Ingredient g) is a sweetener such as aspartame and saccharin.

Ingredient h) is an antioxidant such as butylated hydroxyanisole,butylated hydroxytoluene, and vitamin E.

Ingredient j) is a preservative such as phenol, alkyl esters ofparahydroxybenzoic acid, benzoic acid and the salts thereof, boric acidand the salts thereof, sorbic acid and the salts thereof, chorbutanol,benzyl alcohol, thimerosal, phenylmercuric acetate and nitrate,nitromersol, benzalkonium chloride, cetylpyridinium chloride, methylparaben, and propyl paraben. Particularly preferred are the salts ofbenzoic acid, cetylpyridinium chloride, methyl paraben and propylparaben, and sodium benzoate.

Ingredient k) is a glidant such as silicon dioxide.

Ingredient m) is a solvent, such as water, isotonic saline, ethyloleate, alcohols such as ethanol, glycerin, glycols (e.g., polypropyleneglycol and polyethylene glycol), and buffer solutions (e.g., phosphate,potassium acetate, boric carbonic, phosphoric, succinic, malic,tartaric, citric, acetic, benzoic, lactic, glyceric, gluconic, glutaricand glutamic).

Ingredient n) is a suspending agent. Suitable suspending agents includeAVICEL® RC-591 from FMC Corporation of Philadelphia, Pa. and sodiumalginate.

Ingredient o) lecithin, polysorbate 80, sodium lauryl sulfate,polyoxyethylene sorbitan fatty acid esters, polyoxyethylene monoalkylethers, sucrose monoesters, lanolin esters, and lanolin ethers. Suitablesurfactants are known in the art and commercially available, e.g., theTWEENS® from Atlas Powder Company of Wilmington, Del.

Compositions for parenteral administration typically comprise A) 0.1 to10% of a PGF and B) 90 to 99.9% of a carrier comprising a) a diluent andm) a solvent. Preferably, component a) is propylene glycol and m) isethanol or ethyl oleate.

Compositions for oral administration can have various dosage forms. Forexample, solid forms include tablets, capsules, granules, and bulkpowders. These oral dosage forms comprise a safe and effective amount,usually at least 5%, and preferably from 25% to 50%, of A) the PGF. Theoral dosage compositions further comprise B) 50 to 95% of a carrier,preferably 50 to 75%.

Tablets can be compressed, tablet triturates, enteric-coated,sugar-coated, film-coated, or multiple-compressed. Tablets typicallycomprise A) the PGF, and B) a carrier comprising ingredients selectedfrom the group consisting of a) diluents, b) lubricants, c) binders, d)disintegrants, e) colorants, f) flavors, g) sweeteners, k) glidants, andcombinations thereof. Preferred diluents include calcium carbonate,sodium carbonate, mannitol, lactose and cellulose. Preferred bindersinclude starch, gelatin, and sucrose. Preferred disintegrants includealginic acid, and croscarmelose. Preferred lubricants include magnesiumstearate, stearic acid, and talc. Preferred colorants are the FD&C dyes,which can be added for appearance. Chewable tablets preferably containg) sweeteners such as aspartame and saccharin, or f) flavors such asmenthol, peppermint, and fruit flavors.

Capsules (including time release and sustained release formulations)typically comprise A) the PGF, and B) a carrier comprising one or morea) diluents disclosed above in a capsule comprising gelatin. Granulestypically comprise A) the PGF, and preferably further comprise k)glidants such as silicon dioxide to improve flow characteristics.

The selection of ingredients in the carrier for oral compositionsdepends on secondary considerations like taste, cost, and shelfstability, which are not critical for the purposes of this invention.One skilled in the art can optimize appropriate ingredients withoutundue experimentation.

The solid compositions may also be coated by conventional methods,typically with pH or time-dependent coatings, such that A) the PGF isreleased in the gastrointestinal tract at various times to extend thedesired action. The coatings typically comprise one or more componentsselected from the group consisting of cellulose acetate phthalate,polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate,ethyl cellulose, EUDRAGIT® coatings (available from Rohm & Haas G.M.B.H.of Darmstadt, Germany), waxes and shellac.

Compositions for oral administration can also have liquid forms. Forexample, suitable liquid forms include aqueous solutions, emulsions,suspensions, solutions reconstituted from non-effervescent granules,suspensions reconstituted from non-effervescent granules, effervescentpreparations reconstituted from effervescent granules, elixirs,tinctures, syrups, and the like. Liquid orally administered compositionstypically comprise A) the PGF and B) a carrier comprising ingredientsselected from the group consisting of a) diluents, e) colorants, and f)flavors, g) sweeteners, j) preservatives, m) solvents, n) suspendingagents, and o) surfactants. Peroral liquid compositions preferablycomprise one or more ingredients selected from the group consisting ofe) colorants, f) flavors, and g) sweeteners.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as a) diluents including sucrose, sorbitol and mannitol; and c)binders such as acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropyl methyl cellulose. Such compositions mayfurther comprise b) lubricants, e) colorants, f) flavors, g) sweeteners,h) antioxidants, and k) glidants.

The compositions may further comprise component C) an optional activityenhancer. Component C) is preferably selected from the group consistingof i) hair growth stimulants (other than the PGF) and ii) penetrationenhancers.

Component i) is an optional hair growth stimulant. Component i) isexemplified by vasodilators, antiandrogens, cyclosporins, cyclosporinanalogs, antimicrobials, anti-inflammatories, thyroid hormones, thyroidhormone derivatives, and thyroid hormone analogs, non-selectiveprostaglandin agonists or antagonists, retinoids, triterpenes,combinations thereof, and others. “Non-selective prostaglandin” agonistsand antagonists differ from component A) in that they do not selectivelyactivate the FP receptor, and they may activate other receptors.

Vasodilators such as potassium channel agonists including minoxidil andminoxidil derivatives such as aminexil and those described in U.S. Pat.Nos. 3,382,247, 5,756,092, 5,772,990, 5,760,043, 5,466,694, 5,438,058,4,973,474, and cromakalin and diazoxide can be used as optional hairgrowth stimulants in the composition.

Examples of suitable antiandrogens include 5-α-reductase inhibitors suchas finasteride and those described in U.S. Pat. No. 5,516,779, and inNane et al., Cancer Research 58, “Effects of Some Novel Inhibitors ofC17,20-Lyase and 5α-Reductase in vitro and in vivo and Their PotentialRole in the Treatment of Prostate Cancer,” as well as cyproteroneacetate, azelaic acid and its derivatives and those compounds describedin U.S. Pat. No. 5,480,913, flutamide, and those compounds described inU.S. Pat. Nos. 5,411,981, 5,565,467, and 4,910,226.

Antimicrobials include selenium sulfide, ketoconazole, triclocarbon,triclosan, zinc pyrithione, itraconazole, asiatic acid, hinokitiol,mipirocin and those described in EPA 0,680,745, clinacycinhydrochloride, benzoyl peroxide, benzyl peroxide and minocyclin.

Examples of suitable anti-inflammatories include glucocorticoids such ashydrocortisone, mometasone furoate and prednisolone, nonsteroidalanti-inflammatories including cyclooxygenase or lipoxygenase inhibitorssuch as those described in U.S. Pat. No. 5,756,092, and benzydamine,salicylic acid, and those compounds described in EPA 0,770,399,published May 2, 1997, WO 94/06434, published Mar. 31, 1994, and FR2,268,523, published Nov. 21, 1975.

3,5,3′-Triiodothyronine is an example of a suitable thyroid hormone.

Examples of suitable non-selective prostaglandin agonists andantagonists include compounds such as those described in WO 98/33497,Johnstone, published Aug. 6, 1998, WO 95/11003, Stjemschantz, publishedApr. 27, 1995, JP 97-100091, Ueno and JP 96-134242, Nakamura.

Suitable retinoids include isotretinoin, acitretin, and tazarotene.

Other optional hair growth stimulants for component i) includebenzalkonium chloride, benzethonium chloride, phenol, estradiol,chlorpheniramine maleate, chlorophyllin derivatives, cholesterol,salicylic acid, cysteine, methionine, red pepper tincture, benzylnicotinate, D,L-menthol, peppermint oil, calcium pantothenate,panthenol, castor oil, prednisolone, resorcinol, chemical activators ofprotein kinase C, glycosaminoglycan chain cellular uptake inhibitors,inhibitors of glycosidase activity, glycosaminoglycanase inhibitors,esters of pyroglutamic acid, hexosaccharic acids or acylatedhexosaccharic acids, aryl-substituted ethylenes, N-acylated amino acids,flavinoids, ascomycin derivatives and analogs, histamine antagonistssuch as diphenhydramine hydrochloride, triterpenes such as oleanolicacid and ursolic acid and those described in U.S. Pat. Nos. 5,529,769,5,468,888, 5,631,282, and 5,679,705, JP 10017431, WO 95/35103, JP09067253, WO 92/09262, JP 62093215, and JP 08193094; saponins such asthose described in EP 0,558,509 to Bonte et al., published Sep. 8, 1993and WO 97/01346 to Bonte et al, published Jan. 16, 1997, proteoglycanaseor glycosaminoglycanase inhibitors such as those described in U.S. Pat.Nos. 5,015,470, 5,300,284, and 5,185,325, estrogen agonists andantagonists, pseudoterins, cytokine and growth factor promoters, analogsor inhibitors such as interleukin 1 inhibitors, interleukin-6inhibitors, interleukin-10 promoters, and tumor necrosis factorinhibitors, vitamins such as vitamin D analogs and parathyroid hormoneantagonists, Vitamin B12 analogs and panthenol, interferon agonists andantagonists, hydroxyacids such as those described in U.S. Pat. No.5,550,158, benzophenones, and hydantoin anticonvulsants such asphenyloin, and combinations thereof.

Other additional hair growth stimulants are described in JP 09-157,139to Tsuji et al., published Jun. 17, 1997; EP 0277455 A1 to Mirabeau,published Aug. 10, 1988; WO 97/05887 to Cabo Soler et al., publishedFeb. 20, 1997; WO 92/16186 to Bonte et al., published Mar. 13, 1992; JP62-93215 to Okazaki et al., published Apr. 28, 1987; U.S. Pat. No.4,987,150 to Kurono et al., issued Jan. 22, 1991; JP 290811 to Ohba etal., published Oct. 15, 1992; JP 05-286,835 to Tanaka et al., publishedNov. 2, 1993, FR 2,723,313 to Greff, published Aug. 2, 1994, U.S. Pat.No. 5,015,470 to Gibson, issued May 14, 1991, U.S. Pat. No. 5,559,092,issued Sep. 24, 1996, U.S. Pat. No. 5,536,751, issued Jul. 16, 1996,U.S. Pat. No. 5,714,515, issued Feb. 3, 1998, EPA 0,319,991, publishedJun. 14, 1989, EPA 0,357,630, published Oct. 6, 1988, EPA 0,573,253,published Dec. 8, 1993, JP 61-260010, published Nov. 18, 1986, U.S. Pat.No. 5,772,990, issued Jun. 30, 1998, U.S. Pat. No. 5,053,410, issuedOct. 1, 1991, and U.S. Pat. No. 4,761,401, issued Aug. 2, 1988.

The most preferred activity enhancers are minoxidil and finasteride,most preferably minoxidil.

Component ii) is a penetration enhancer that can be added to all of thecompositions for systemic administration. The amount of component ii),when present in the composition, is typically 1 to 5%. Examples ofpenetration enhancers include 2-methyl propan-2-ol, propan-2-ol,ethyl-2-hydroxypropanoate, hexan-2,5-diol, polyoxyethylene(2) ethylether, di(2-hydroxypropyl)ether, pentan-2,4-diol, acetone,polyoxyethylene(2) methyl ether, 2-hydroxypropionic acid,2-hydroxyoctanoic acid, propan-1-ol, 1,4-dioxane, tetrahydrofuran,butan-1,4-diol, propylene glycol dipelargonate, polyoxypropylene 15stearyl ether, octyl alcohol, polyoxyethylene ester of oleyl alcohol,oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate,di-isopropyl adipate, di-isopropyl sebacate, dibutyl sebacate, diethylsebacate, dimethyl sebacate, dioctyl sebacate, dibutyl suberate, dioctylazelate, dibenzyl sebacate, dibutyl phthalate, dibutyl azelate, ethylmyristate, dimethyl azelate, butyl myristate, dibutyl succinate, didecylphthalate, decyl oleate, ethyl caproate, ethyl salicylate, isopropylpalmitate, ethyl laurate, 2-ethyl-hexyl pelargonate, isopropylisostearate, butyl laurate, benzyl benzoate, butyl benzoate, hexyllaurate, ethyl caprate, ethyl caprylate, butyl stearate, benzylsalicylate, 2-hydroxypropanoic acid, 2-hydroxyoctanoic acid, dimethylsulphoxide, N,N-dimethyl acetamide, N,N-dimethyl formamide,2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone,1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, phosphine oxides,sugar esters, tetrahydrofurfural alcohol, urea, diethyl-m-toluamide,1-dodecylazacyloheptan-2-one, omega three fatty acids and fish oils, andcombinations thereof.

In a preferred embodiment of the invention, the PGF's are topicallyadministered. Topical compositions that can be applied locally to theskin may be in any form including solutions, oils, creams, ointments,gels, lotions, shampoos, leave-on and rinse-out hair conditioners,milks, cleansers, moisturizers, sprays, skin patches, and the like.Topical compositions comprise: component A) the PGF described above andcomponent B) a carrier. The carrier of the topical compositionpreferably aids penetration of the PGF's into the skin to reach theenvironment of the hair follicle. Component B) may further comprise oneor more optional components. Topical compositions preferably furthercomprise C) one or more of the optional activity enhancers describedabove.

The exact amounts of each component in the topical composition depend onvarious factors. The amount of component A) depends on the IC₅₀ of thePGF selected. “IC₅₀” means inhibitory concentration 50^(th) percentile.The amount of component A) added to the topical composition is:

IC ₅₀×10⁻²≧% of component A)≧IC ₅₀×10⁻³,

where IC₅₀ is expressed in nanomolar units. For example, if the IC₅₀ ofthe PGF is 1 nM, the amount of component A) will be 0.001 to 0.01%. Ifthe IC₅₀ of the PGF is 10 nM, the amount of component A) will be 0.01 to0.1%. If the IC₅₀ of the PGF is 100 nM, the amount of component A) willbe 0.1 to 1.0%. If the IC₅₀ of the PGF is 1000 nM, the amount ofcomponent A) will be 1.0 to 10%, preferably 1.0 to 5%. If the amount ofcomponent A) is outside the ranges specified above (i.e., either higheror lower), efficacy of the treatment may be reduced. IC₅₀ can becalculated according to the method in Reference Example 1, below. Oneskilled in the art can calculate IC₅₀ without undue experimentation.

The topical composition preferably further comprises 1 to 20% componentC), and a sufficient amount of component B) such that the amounts ofcomponents A), B), and C), combined equal 100%. The amount of B) thecarrier employed in conjunction with the PGF is sufficient to provide apractical quantity of material for administration per unit dose of thecompound. Techniques and compositions for making dosage forms useful inthe methods of this invention are described in the following references:Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); andAnsel, Introduction to Pharmaceutical Dosage Forms, 2^(nd) Ed., (1976).

Component B) the carrier may comprise a single ingredient or acombination of two or more ingredients. In the topical compositions,component B) is a topical carrier. Preferred topical carriers compriseone or more ingredients selected from the group consisting of water,alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils,mineral oil, propylene glycol, polypropylene glycol-2 myristylpropionate, dimethyl isosorbide, combinations thereof, and the like.More preferred carriers include propylene glycol, dimethyl isosorbide,and water.

The topical carrier may comprise one or more ingredients selected fromthe group consisting of q) emollients, r) propellants, s) solvents, t)humectants, u) thickeners, v) powders, and w) fragrances in addition to,or instead of, the preferred topical carrier ingredients listed above.One skilled in the art would be able to optimize carrier ingredients forthe topical compositions without undue experimentation.

Ingredient q) is an emollient. The amount of ingredient q) in thetopical composition is typically 5 to 95%. Suitable emollients includestearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate,propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropylisostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleylalcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol,isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropylmyristate, isopropyl palmitate, isopropyl stearate, butyl stearate,polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconutoil, arachis oil, castor oil, acetylated lanolin alcohols, petrolatum,mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyllinoleate, lauryl lactate, myristyl lactate, decyl oleate, myristylmyristate, polydimethylsiloxane, and combinations thereof. Preferredemollients include stearyl alcohol and polydimethylsiloxane.

Ingredient r) is a propellant. The amount of ingredient r) in thetopical composition is typically 5 to 95%. Suitable propellants includepropane, butane, isobutane, dimethyl ether, carbon dioxide, nitrousoxide, and combinations thereof. Ingredient s) is a solvent. The amountof ingredient s) in the topical composition is typically 5 to 95%.Suitable solvents include water, ethyl alcohol, methylene chloride,isopropanol, castor oil, ethylene glycol monoethyl ether, diethyleneglycol monobutyl ether, diethylene glycol monoethyl ether,dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinationsthereof. Preferred solvents include ethyl alcohol.

Ingredient t) is a humectant. The amount of ingredient t) in the topicalcomposition is typically 5 to 95%. Suitable humectants include glycerin,sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutylphthalate, gelatin, and combinations thereof. Preferred humectantsinclude glycerin.

Ingredient u) is a thickener. The amount of ingredient u) in the topicalcomposition is typically 0 to 95%.

Ingredient v) is a powder. The amount of ingredient v) in the topicalcomposition is typically 0 to 95%. Suitable powders include chalk, talc,fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodiumpolyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammoniumsmectites, chemically modified magnesium aluminum silicate, organicallymodified montmorillonite clay, hydrated aluminum silicate, fumed silica,carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycolmonostearate, and combinations thereof.

Ingredient w) is a fragrance. The amount of ingredient w) in the topicalcomposition is typically 0.001 to 0.5%, preferably 0.001 to 0.1%.

Component C) the optional activity enhancer is as described above. Anyof the i) hair growth stimulants and ii) penetration enhancers may beadded to the topical compositions. Preferably, the topical compositioncomprises 0.01 to 15% of component i) the optional hair growthstimulant. More preferably, the composition comprises 0.1 to 10%, andmost preferably 0.5 to 5% of component i). Preferably, the topicalcomposition comprises 1 to 5% of component ii).

In an alternative embodiment of the invention, topical pharmaceuticalcompositions for ocular administration are prepared by conventionalmethods. Topical pharmaceutical compositions for ocular administrationtypically comprise A) a PGF, B) a carrier, such as purified water, andone or more ingredients selected from the group consisting of y) sugarssuch as dextrans, particularly dextran 70, z) cellulose or a derivativethereof, aa) a salt, bb) disodium EDTA (Edetate disodium), and cc) a pHadjusting additive.

Examples of z) cellulose derivatives suitable for use in the topicalpharmaceutical composition for ocular administration include sodiumcarboxymethyl cellulose, ethyl cellulose, methyl cellulose, andhydroxypropylmethylcellulose. Hydroxypropylmethylcellulose is preferred.

Examples of aa) salts suitable for use in the for use in the topicalpharmaceutical composition for ocular administration include sodiumchloride, potassium chloride, and combinations thereof.

Examples of cc) pH adjusting additives include HCl or NaOH in amountssufficient to adjust the pH of the topical pharmaceutical compositionfor ocular administration to 7.2-7.5.

This invention further relates to a method for darkening hair,thickening hair, and reversing hair graying. The method comprisesapplying the topical composition for treating hair loss to hair, to skinin the locus of hair, or both. For example, the topical composition maybe applied to hair growing on the scalp or eyelashes. The topicalcomposition can be, for example, a cosmetic composition prepared asdescribed above. An example of a composition that may be applied toeyelashes is a mascara. The prostaglandin may be added to mascaracompositions known in the art, such as the mascara described in U.S.Pat. No. 5,874,072, which is hereby incorporated by reference. Themascara comprises dd) a water-insoluble material, ee) a water-soluble,film-forming polymer, ff) a wax, o) a surfactant, gg) a pigment, and s)a solvent.

Ingredient dd) is a water-insoluble material selected from the groupconsisting of acrylate copolymers; styrene/acrylate/methacrylatecopolymers; acrylic latex; styrene/acrylic ester copolymer latex;polyvinylacetate latex; vinyl acetate/ethylene copolymer latex;styrene/butadiene copolymer latex; polyurethane latex;butadiene/acrylonitrile copolymer latex; styrene/acrylate/acrylonitrilecopolymer latex; and mixtures thereof, wherein the acrylate copolymers,and the styrene/acrylate/methacrylate copolymers additionally compriseammonia, propylene glycol, a preservative and a surfactant.

Ingredient ee) is a water-soluble, film-forming polymer. Ingredient ee)is selected from the group consisting of vinylalcohol/poly(alkyleneoxy)acrylate, vinyl alcohol/vinylacetate/poly-(alkyleneoxy)acrylate, polyethylene oxide, polypropyleneoxide, acrylates/octyl-acrylamide copolymers and mixtures thereof.

Ingredient ff) is a wax. “Wax” means a lower-melting organic mixture orcompound of high molecular weight, solid at room temperature andgenerally similar in composition to fats and oils except that theycontain no glycerides. Some are hydrocarbons, others are esters of fattyacids and alcohols. Waxes useful in this invention are selected from thegroup consisting of animal waxes, vegetable waxes, mineral waxes,various fractions of natural waxes, synthetic waxes, petroleum waxes,ethylenic polymers, hydrocarbon types such as Fischer-Tropsch waxes,silicone waxes, and mixtures thereof wherein the waxes have a meltingpoint between 55 and 100° C.

Ingredient o) is surfactant, as described above. Ingredient o) in themascara is preferably a surfactant having an HLB from 3 to 15. Suitablesurfactants include those disclosed in the C.T.F.A. Cosmetic IngredientHandbook, pp. 587-592 (1992); Remington's Pharmaceutical Sciences, 15thEd. pp. 335-337 (1975); and McCutcheon's Volume 1, Emulsifiers &Detergents, North American Edition, pp. 236-239 (1994).

Ingredient gg) is a pigment. Suitable pigments include inorganicpigments, organic lake pigments, pearlescent pigments, and mixturesthereof. Inorganic pigments useful in this invention include thoseselected from the group consisting of rutile or anatase titaniumdioxide, coded in the Color Index under the reference CI 77,891; black,yellow, red and brown iron oxides, coded under references CI 77,499,77,492 and, 77,491; manganese violet (CI 77,742); ultramarine blue (CI77,007); chromium oxide (CI 77,288); chromium hydrate (CI 77,289); andferric blue (CI 77,510) and mixtures thereof.

The organic pigments and lakes useful in this invention include thoseselected from the group consisting of D&C Red No. 19 (CI 45,170), D&CRed No. 9 (CI 15,585), D&C Red No. 21 (CI 45,380), D&C Orange No. 4 (CI15,510), D&C Orange No. 5 (CI 45,370), D&C Red No. 27 (CI 45,410), D&CRed No. 13 (CI 15,630), D&C Red No. 7 (CI 15,850), D&C Red No. 6 (CI15,850), D&C Yellow No. 5 (CI 19,140), D&C Red No. 36 (CI 12,085), D&COrange No. 10 (CI 45,425), D&C Yellow No. 6 (CI 15,985), D&C Red No. 30(CI 73,360), D&C Red No. 3 (CI 45,430) and the dye or lakes based onCochineal Carmine (CI 75,570) and mixtures thereof.

The pearlescent pigments useful in this invention include those selectedfrom the group consisting of the white pearlescent pigments such as micacoated with titanium oxide, bismuth oxychloride, colored pearlescentpigments such as titanium mica with iron oxides, titanium mica withferric blue, chromium oxide and the like, titanium mica with an organicpigment of the above-mentioned type as well as those based on bismuthoxychloride and mixtures thereof.

Ingredient s) is a solvent described above, preferably water.

The amount of A) the PGF added to the mascara is as described above fortopical compositions.

The PGF's may also be administered in the form of liposome deliverysystems, such as small unilamellar vesicles, large unilamellar vesicles,and multilamellar vesicles. Liposomes can be formed from a variety ofphospholipids, such as cholesterol, stearylamine orphosphatidylcholines. A preferred formulation for topical delivery ofthe present compounds uses liposomes as described in Dowton et al.,“Influence of Liposomal Composition on Topical Delivery of EncapsulatedCyclosporin A: I. An in vitro Study Using Hairless Mouse Skin”, S.T.P.Pharma Sciences, Vol. 3, pp. 404-407 (1993); Wallach and Philippot, “NewType of Lipid Vesicle: Novasome®”, Liposome Technology, Vol. 1, pp.141-156 (1993); Wallach, U.S. Pat. No. 4,911,928, assigned to Micro-Pak,Inc., issued Mar. 27, 1990; and Weiner et al., U.S. Pat. No. 5,834,014,assigned to The University of Michigan and Micro-Pak, Inc., issued Nov.10, 1998 (with respect to Weiner et al., with a compound as describedherein administered in lieu of, or in addition to, minoxidil).

The PGF's may also be administered by iontophoresis. See, e.g., Internetsite www.unipr.it/arpa/dipfarm/erasmus/erasm14.html; Banga et al.,“Hydrogel-based Iontotherapeutic Delivery Devices for TransdermalDelivery of Peptide/Protein Drugs”, Pharm. Res., Vol. 10 (5), pp.697-702 (1993); Ferry, “Theoretical Model of Iontophoresis Utilized inTransdermal Drug Delivery”, Pharmaceutical Acta Helvetiae, Vol 70, pp.279-287 (1995); Gangarosa et al., “Modern Iontophoresis for Local DrugDelivery”, Int. J. Pharm, Vol. 123, pp. 159-171 (1995); Green et al.,“Iontophoretic Delivery of a Series of Tripeptides Across the Skin invitro”, Pharm. Res., Vol 8, pp. 1121-1127 (1991); Jadoul et al.,“Quantification and Localization of Fentanyl and TRH Delivered byIontophoresis in the Skin”, Int. J. Pharm., Vol. 120, pp. 221-8 (1995);O'Brien et al., “An Updated Review of its Antiviral Activity,Pharmacokinetic Properties and Therapeutic Efficacy”, Drugs, Vol. 37,pp. 233-309 (1989); Parry et al., “Acyclovir Biovailability in HumanSkin”, J. Invest. Dermatol., Vol. 98 (6), pp. 856-63 (1992); Santi etal., “Drug Reservoir Composition and Transport of Salmon Calcitonin inTransdermal Iontophoresis”, Pharm. Res., Vol 14 (1), pp. 63-66 (1997);Santi et al., “Reverse Iontophoresis—Parameters DeterminingElectroosmotic Flow: I. pH and Ionic Strength”, J. Control. Release,Vol. 38, pp. 159-165 (1996); Santi et al., “ReverseIontophoresis—Parameters Determining Electroosmotic Flow: II. ElectrodeChamber Formulation”, J. Control. Release, Vol. 42, pp. 29-36 (1996);Rao et al., “Reverse Iontophoresis: Noninvasive Glucose Monitoring invivo in Humans”, Pharm. Res., Vol. 12 (12), pp. 1869-1873 (1995);Thysman et al., “Human Calcitonin Delivery in Rats by Iontophoresis”, J.Pharm. Pharmacol., Vol. 46, pp. 725-730 (1994); and Volpato et al.,“Iontophoresis Enhances the Transport of Acyclovir through Nude MouseSkin by Electrorepulsion and Electroosmosis”, Pharm. Res., Vol. 12 (11),pp. 1623-1627 (1995).

The PGF's may be included in kits comprising a PGF, a systemic ortopical composition described above, or both; and information,instructions, or both that use of the kit will provide treatment forhair loss in mammals (particularly humans). The information andinstructions may be in the form of words, pictures, or both, and thelike. In addition or in the alternative, the kit may comprise a PGF, acomposition, or both; and information, instructions, or both, regardingmethods of application of the PGF or composition, preferably with thebenefit of treating hair loss in mammals.

In all of the foregoing compositions, and for all routes ofadministration, the PGF's can be used alone or in combinations of two ormore PGF's. The compositions may further comprise additional drugs orexcipients as appropriate for the indication.

METHODS OF THE INVENTION

This invention further relates to a method for treating hair loss inmammals. The method comprises administering to a mammal (preferably ahuman) suffering from hair loss, a PGF described above. For example, amammal diagnosed with alopecia including male pattern baldness andfemale pattern baldness can be treated by the methods of this invention.Preferably, a systemic or topical composition comprising A) the PGF andB) a carrier is administered to the mammal. More preferably, thecomposition is a topical composition comprising A) the PGF, B) thecarrier, and C) an optional activity enhancer.

The dosage of the PGF administered depends on the method ofadministration. For systemic administration, (e.g., oral, rectal, nasal,sublingual, buccal, or parenteral), typically, 0.5 mg to 300 mg,preferably 0.5 mg to 100 mg, more preferably 0.1 mg to 10 mg, of a PGFdescribed above is administered per day. These dosage ranges are merelyexemplary, and daily administration can be adjusted depending on variousfactors. The specific dosage of the PGF to be administered, as well asthe duration of treatment, and whether the treatment is topical orsystemic are interdependent. The dosage and treatment regimen will alsodepend upon such factors as the specific PGF used, the treatmentindication, the efficacy of the compound, the personal attributes of thesubject (such as, for example, weight, age, sex, and medical conditionof the subject), compliance with the treatment regimen, and the presenceand severity of any side effects of the treatment.

For topical administration (e.g., local application on the skin, ocular,liposome delivery systems, or iontophoresis), the topical composition istypically administered once per day. The topical compositions areadministered daily for a relatively short amount of time (i.e., on theorder of weeks). Generally, 6 to 12 weeks is sufficient. The topicalcompositions are preferably leave-on compositions. In general, thetopical composition should not be removed for at least several hoursafter administration.

In addition to the benefits in treating hair loss, the inventors havesurprisingly found that the PGF's in the compositions and methods ofthis invention also darken and thicken hair and may reverse hairgraying.

EXAMPLES

These examples are intended to illustrate the invention to those skilledin the art and should not be interpreted as limiting the scope of theinvention set forth in the claims.

Reference Example 1 Radioligand Binding Assay

IC₅₀ of a PGF can be determined relative to PGF₂, using the RadioligandBinding Assay. As a control, the IC₅₀ for PGF₂, itself should be nolower than 1.0 nM and no higher than 5.0 nM.

In this assay, COS-7 cells are transiently transfected with the hFPrecombinant plasmid using LipofectAMINE Reagent. Forty-eight hourslater, the transfected cells are washed with Hank's Balanced SaltSolution (HBSS, without CaCl₂, MgCl₂, MgSO₄, or phenol red). The cellsare detached with versene, and HBSS is added. The mixture is centrifugedat 200 g for 10 minutes, at 4° C. to pellet the cells. The pellet isresuspended in Phosphate-Buffered Saline-EDTA buffer (PBS; 1 mM EDTA; pH7.4; 4° C.). The cells are disrupted by nitrogen cavitation (Parr model4639), at 800 psi, for 15 minutes at 4° C. The mixture is centrifuged at1000 g for 10 minutes at 4° C. The supernatant is centrifuged at 100,000g for 60 minutes at 4° C. The pellet is resuspended to 1 mg protein/mLTME buffer (50 mM Tris; 10 mM MgCl₂; 1 mM EDTA; pH 6.0; 4° C.) based onprotein levels measured using the Pierce BCA Protein Assay kit. Thehomogenate is mixed for 10 seconds using a Kinematica POLYTRON®(available from KINEMATICA AG, Luzernerstrasse 147A CH-6014 Littau,Switzerland). The membrane preparations are then stored at −80° C.,until thawed for assay use.

The receptor competition binding assays are developed in a 96 wellformat. Each well contains 100 g of hFP membrane, 5 nM (3H) PGF2, andthe various competing compounds in a total volume of 200 L. The platesare incubated at 23° C. for 1 hour. The incubation is terminated byrapid filtration using the Packard Filtermate 196 harvester throughPackard UNIFILTER® GF/B filters (available from Packard Instrument Co.,Inc. of Downers Grove Ill.) pre-wetted with TME buffer. The filter iswashed four times with TME buffer. Packard Microscint 20, a highefficiency liquid scintillation cocktail, is added to the filter platewells and the plates remain at room temperature for three hours prior tocounting. The plates are read on a Packard TOPCOUNT® MicroplateScintillation Counter (also available from Packard Instrument Co., Inc.)

Reference Example 2 Telogen Conversion Assay

PGF's are tested for their potential to grow hair using the TelogenConversion Assay. The Telogen Conversion Assay measures the potential ofa PGF to convert mice in the resting stage of the hair growth cycle(“telogen”), to the growth stage of the hair growth cycle (“anagen”).

Without intending to be limited by theory, there are three principalphases of the hair growth cycle: anagen, catagen, and telogen. It isbelieved that there is a longer telogen period in C3H mice (HarlanSprague Dawley, Inc., Indianapolis, Ind.) from approximately 40 days ofage until about 75 days of age, when hair growth is synchronized. It isbelieved that after 75 days of age, hair growth is no longersynchronized. Wherein about 40 day-old mice with dark fur (brown orblack) are used in hair growth experiments, melanogenesis occurs alongwith hair (fur) growth wherein the topical application of hair growthinducers are evaluated. The Telogen Conversion Assay herein is used toscreen PGF's for potential hair growth by measuring melanogenesis.

Three groups of 44 day-old C3H mice are used: a vehicle control group, apositive control group, and a test PGF group, wherein the test PGF groupis administered a PGF used in the method of this invention. The lengthof the assay is 24 days with 15 treatment days (wherein the treatmentdays occur Mondays through Fridays). Day 1 is the first day oftreatment. A typical study design is shown in Table 1 below. Typicaldosage concentrations are set forth in Table 1, however the skilledartisan will readily understand that such concentrations may bemodified.

TABLE 1 Assay Parameters Group Animal Concen- Application Length # #Compound tration volume of Study 1  1-10 Test 0.01% in 400 μL 26 daysCompound vehicle** topical 2 11-20 Positive 0.01% in 400 μL 26 daysControl vehicle** topical (T3)* 3 21-30 Vehicle** N/A 400 μL 26 daystopical *T3 is 3,5,3′-triiodothyronine. **The vehicle is 60% ethanol,20% propylene glycol, and 20% dimethyl isosorbide (commerciallyavailable from Sigma Chemical Co., St. Louis, MO).

The mice are treated topically Monday through Friday on their lower back(base of tail to the lower rib). A pipettor and tip are used to deliver400 μL to each mouse's back. The 400 μL application is applied slowlywhile moving hair on the mouse to allow the application to reach theskin.

While each treatment is being applied to the mouse topically, a visualgrade of from 0 to 4 will be given to the skin color in the applicationarea of each animal. As a mouse converts from telogen to anagen, itsskin color will become more bluish-black. As indicated in Table 2, thegrades 0 to 4 represent the following visual observations as the skinprogresses from white to bluish-black.

TABLE 2 Evaluation Criteria Visual Observation Grade Whitish Skin Color0 Skin is light gray (indication of initiation of anagen) 1 Appearanceof Blue Spots 2 Blue Spots are aggregating to form one large blue area 3Skin is dark blue (almost black) with color covering majority of 4treatment area (indication of mouse in full anagen)

Example 1

A PGF having the structure:

was tested according to the method of Reference Example 1. The averagegrade was calculated by averaging the grades of 7 mice after 23 days, 25days, and 26 days. The results are in Table 3. The PGF grew hair.

Example 2

A PGF having the structure:

was tested according to the method of Reference Example 1. The averagegrade was calculated by averaging the grades of 7 mice after 23 days.The results are in Table 3. The PGF grew hair.

TABLE 3 Average Grades Example 23 Days 25 Days 26 Days 1 0.4 0.1 0.7 20.1 not measured not measured

Example 3

Compositions for topical administration are made, comprising:

Component 3-1 3-2 3-3 PGF (wt %) 0.07 0.1 2.4 IC₅₀ the PGF (nM) 7 10 24Ethanol (wt %) 59.958 59.9 58.6 Propylene Glycol (wt %) 19.986 20.0 19.5Dimethyl Isosorbide (wt %) 19.986 20.0 19.5

The PGFs in the compositions are as follows:

Sample PGF 3-1

3-2

3-3

A human male subject suffering from male pattern baldness is treated bya method of this invention. Specifically, for 6 weeks, one of the abovecompositions is daily administered topically to the subject to inducehair growth.

Example 4

A composition for topical administration is made according to the methodof Dowton et al., “Influence of Liposomal Composition on TopicalDelivery of Encapsulated Cyclosporin A: I. An in vitro Study UsingHairless Mouse Skin”, S.T.P. Pharma Sciences, Vol. 3, pp. 404-407(1993), using a PGF in lieu of cyclosporin A and using the NOVASOME® 1(available from Micro-Pak, Inc. of Wilmington, Del.) for the non-ionicliposomal formulation.

A human male subject suffering from male pattern baldness is treatedeach day with the above composition. Specifically, for 6 weeks, theabove composition is administered topically to the subject.

Example 5

Shampoos are made, comprising:

Component Ex. 5-1 Ex. 5-2 Ex. 5-3 Ex. 5-4 Ammonium Lauryl Sulfate11.5%   11.5%   9.5%   7.5%   Ammonium Laureth Sulfate 4% 3% 2% 2%Cocamide MEA 2% 2% 2% 2% Ethylene Glycol Distearate 2% 2% 2% 2% CetylAlcohol 2% 2% 2% 2% Stearyl Alcohol 1.2%   1.2%   1.2%   1.2%   Glycerin1% 1% 1% 1% Polyquaternium 10 0.5%   0.25%   — — Polyquaternium 24 — —0.5%   0.25%   Sodium Chloride 0.1%   0.1%   0.1%   0.1%   SucrosePolyesters of Cottonate Fatty 3% 3% — — Acid Sucrose Polyesters ofBehenate Fatty Acid 2% 3% — — Polydimethyl Siloxane — — 3% 2%Cocaminopropyl Betaine — 1% 3% 3% Lauryl Dimethyl Amine Oxide 1.5%  1.5%   1.5%   1.5%   Decyl Polyglucose — — 1% 1% DMDM Hydantoin 0.15%  0.15%   0.15%   0.15%   PGF having IC₅₀ of 7 nM — 0.007%    0.007%    —PGF having IC₅₀ of 24 nM 0.024%    — — 0.024%    Minoxidil 3% 2%Phenoxyethanol 0.5%   0.5%   0.5%   0.5%   Fragrance 0.5%   0.5%  0.5%   0.5%   Water q.s. q.s. q.s. q.s.

A human subject suffering from male pattern baldness is treated by amethod of this invention. Specifically, for 12 weeks, a shampoodescribed above is used daily by the subject.

Example 6

A mascara composition is prepared. The composition comprises:

% Component W/W WATER, DEIONIZED, USP q.s. BLACK 1080 MICRONIZED TYPE10.000 GLYCERYL MONOSTEARATE (2400 TYPE) 8.500 C18-36 ACID TRIGLYCERIDE5.500 STEARIC ACID, TRIPLE PRESSED, LIQUID 4.000 ETHYL ALCOHOL SD 40-B,190 4.000 PROOF/SERIAL #: BEESWAX WHITE, FLAKES 3.250 SHELLAC, NF 3.000LECITHIN, GRANULAR (TYPE 6450) 2.500 TRIETHANOLAMINE 99% - TANK 2.470PARAFFIN WAX 2.250 PARAFFIN WAX 118/125 2.250 CARNAUBA WAX, NF 2.000POTASSIUM CETYL PHOSPHATE 1.000 PHENOXYETHANOL 0.800 OLEIC ACID NF 0.750DL-PANTHENOL 0.350 PVP/VA COPOLYMER 0.250 METHYLPARABEN, NF 0.200DIAZOLIDINYL UREA 0.200 SIMETHICONE 0.200 ETHYLPARABEN NF 0.150PENTAERYTHRITYL HYDROGENATED 0.150 ROSINATE PROPYLPARABEN, NF 0.100TRISODIUM EDTA 0.100 PGF having IC₅₀ of 7 nM 0.007The PGF is the same as that in Example 3-1.A human female subject applies the composition each day. Specifically,for 6 weeks, the above composition is administered topically to thesubject to darken and thicken eyelashes.

Example 7

Pharmaceutical compositions in the form of tablets are prepared byconventional methods, such as mixing and direct compaction, formulatedas follows:

Ingredient Quantity (mg per tablet) PGF 0.5 Microcrystalline Cellulose100 Sodium Starch Glycollate 30 Magnesium Stearate 3

The prostaglandin is the same as that in Example 3-3.

The above composition is administered orally to a subject once daily for6 to 12 weeks to promote hair growth.

Example 8

Pharmaceutical compositions in liquid form are prepared by conventionalmethods, formulated as follows:

Ingredient Quantity PGF 0.1 mg Phosphate buffered physiological saline10 ml Methyl Paraben 0.05 ml

The prostaglandin is the same as that in Example 3-3.

1.0 ml of the above composition is administered subcutaneously at thesite of hair loss once daily for 6 to 12 weeks to promote hair growth.

Example 9

A topical pharmaceutical composition is prepared by conventional methodsand formulated as follows:

Ingredient Amount (wt %) PGF 0.004 Dextran 70 0.1 Hydroxypropylmethylcellulose 0.3 Sodium Chloride 0.77 Potassium chloride 0.12Disodium EDTA (Edetate disodium) 0.05 Benzalkonium chloride 0.01 HCLand/or NaOH pH 7.2-7.5 Purified water q.s. to 100%

The prostaglandin is the same as that in Example 3-3.

The above composition is administered ocularly to a subject once per dayfor 6 to 12 weeks to promote eyelash growth.

EFFECTS OF THE INVENTION

The compositions and methods herein provide a cosmetic benefit withrespect to hair growth and appearance in subjects desiring suchtreatment.

1. A topical composition for treating hair loss comprising: A) an activeingredient selected from the group consisting of a prostaglandin Fanalog having the structure

and pharmaceutically acceptable salts and hydrates of the prostaglandinF analog; biohydrolyzable amides, esters, and imides of theprostaglandin F analog; optical isomers, diastereomers, and enantiomersof the prostaglandin F analog; and combinations thereof; wherein R¹ isselected from the group consisting of CO₂H, C(O)NHOH, CO₂R⁵, CH₂OH,S(O)₂R⁵, C(O)NHR⁵, C(O)NHS(O)₂R⁵, and tetrazole; R² is selected from thegroup consisting of a hydrogen atom and a lower monovalent hydrocarbongroup; R³ and R⁴ are each independently selected from the groupconsisting of H, CH₃, C₂H₅, OR¹⁰, SR¹⁰, and OH; with the proviso thatboth R³ and R⁴ are not OH; R⁵ is selected from the group consisting ofmonovalent hydrocarbon groups, substituted monovalent hydrocarbongroups, aromatic groups, substituted aromatic groups, carbocyclicgroups, substituted carbocyclic groups, heterogeneous groups,substituted heterogeneous groups, heterocyclic groups, substitutedheterocyclic groups, heteroaromatic groups, and substitutedheteroaromatic groups; X is selected from the group consisting of NR⁶R⁷,OR⁸, SR⁹, S(O)R⁹, and S(O)₂R⁹; R⁶, R⁷, and R⁸ are each independentlyselected from the group consisting of hydrogen atoms, acyl groups,monovalent hydrocarbon groups, substituted monovalent hydrocarbongroups, heterogeneous groups, substituted heterogeneous groups,carbocyclic groups, substituted carbocyclic groups, aromatic groups,substituted aromatic groups, heteroaromatic groups, and substitutedheteroaromatic groups; R⁹ is selected from the group consisting ofmonovalent hydrocarbon groups, substituted monovalent hydrocarbongroups, heterogeneous groups, substituted heterogeneous groups,carbocyclic groups, substituted carbocyclic groups, heterocyclic groups,substituted heterocyclic groups, aromatic groups, substituted aromaticgroups, heteroaromatic groups, and substituted heteroaromatic groups;R¹⁰ is selected from the group consisting of a monovalent hydrocarbongroup, a substituted monovalent hydrocarbon group, a heterogeneousgroup, a substituted heterogeneous group, a carbocyclic group, asubstituted carbocyclic group, an aromatic group, a substituted aromaticgroup, a heteroaromatic group, and a substituted heteroaromatic group;with the proviso that R¹⁰ has 1 to 8 member atoms; Y is selected fromthe group consisting of an oxygen atom, a divalent hydrocarbon group, asulfur-containing moiety, and a nitrogen-containing group; and Z isselected from the group consisting of a carbocyclic group, a substitutedcarbocyclic group, a heterocyclic group, a substituted heterocyclicgroup, an aromatic group, a substituted aromatic group, a heteroaromaticgroup, and a substituted heteroaromatic group; and B) a carrier.
 2. Thecomposition of claim 1, wherein R¹ is selected from the group consistingof CO₂H, CO₂CH₃, CO₂C₂H₅, CO₂C₃H₇, CO₂C₄H₉, CO₂C₃H₇O₂, andC(O)NHS(O)₂R⁵.
 3. The composition of claim 1, wherein R⁵ is selectedfrom the group consisting of CH₃, C₂H₅, and C₃H₇.
 4. The composition ofclaim 1, wherein R² is selected from the group consisting of a hydrogenatom and a methyl group.
 5. The composition of claim 1, wherein R³ andR⁴ are both hydrogen atoms.
 6. The composition of claim 1, wherein X isselected from the group consisting of NR⁶R⁷ and OR⁸.
 7. The compositionof claim 1, wherein R⁶ and R⁷ are each independently selected from thegroup consisting of H, CH₃, and C₂H₅.
 8. The composition of claim 1,wherein R⁸ is selected from the group consisting of H, CH₃, C₂H₅, andC₃H₇.
 9. The composition of claim 1, wherein R⁹ is selected from thegroup consisting of CH₃ and C₂H₅.
 10. The composition of claim 1,wherein Y is a divalent hydrocarbon group having the formula (CH₂)_(n),wherein n is
 1. 11. The composition of claim 1, wherein Y is selectedfrom the group consisting of a sulfur atom, an oxygen atom, S(O), andS(O)₂.
 12. The composition of claim 1, wherein Y is anitrogen-containing group having the formula NR¹¹; wherein R¹¹ isselected from the group consisting of a hydrogen atom, an acyl group, amonovalent hydrocarbon group, a substituted monovalent hydrocarbongroup, a heterogeneous group, a substituted heterogeneous group, acarbocyclic group, a substituted carbocyclic group, a heterocyclicgroup, a substituted heterocyclic group, an aromatic group, asubstituted aromatic group, a heteroaromatic group, and a substitutedheteroaromatic group.
 13. The composition of claim 1, wherein Z isselected from the group consisting of a monocyclic carbocyclic group, asubstituted monocyclic carbocyclic group, a monocyclic heterocyclicgroup, a substituted monocyclic heterocyclic group, a monocyclicaromatic group, a substituted monocyclic aromatic group, a monocyclicheteroaromatic group, and a substituted monocyclic heteroaromatic group.14. The composition of claim 1, wherein component A) is added in anamount ofIC ₅₀×10⁻²≧% of component A)≧IC ₅₀×10⁻³, where IC₅₀ of component A) isexpressed in nanomolar units.
 15. The composition of claim 1, whereincomponent C) is added to the composition in an amount of 1 to 20%, and asufficient amount of component B) is added such that the amounts ofcomponents A), B), and C) combined equal 100%.
 16. The composition ofclaim 1, wherein component B) comprises an ingredient selected from thegroup consisting of water, alcohols, aloe vera gel, allantoin, glycerin,vitamin A and E oils, mineral oil, propylene glycol, dimethylisosorbide, polypropylene glycol-2 myristyl propionate, q) emollients,r) propellants, s) solvents, t) humectants, u) thickeners, v) powders,w) fragrances, and combinations thereof.
 17. The composition of claim16, wherein ingredient q) is selected from the group consisting ofstearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate,propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropylisostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleylalcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol,isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropylmyristate, isopropyl palmitate, isopropyl stearate, butyl stearate,polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconutoil, arachis oil, castor oil, acetylated lanolin alcohols, petrolatum,mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyllinoleate, lauryl lactate, myristyl lactate, decyl oleate, myristylmyristate, and combinations thereof.
 18. The composition of claim 16,wherein ingredient r) is selected from the group consisting of propane,butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, andcombinations thereof.
 19. The composition of claim 16, whereiningredient s) is selected from the group consisting of water, ethylalcohol, methylene chloride, isopropanol, castor oil, ethylene glycolmonoethyl ether, diethylene glycol monobutyl ether, diethylene glycolmonoethyl ether, dimethyl sulfoxide, dimethyl formamide,tetrahydrofuran, and combinations thereof.
 20. The composition of claim16, wherein ingredient t) is selected from the group consisting ofglycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, solublecollagen, dibutyl phthalate, gelatin, and combinations thereof.
 21. Thecomposition of claim 16, wherein ingredient v) is selected from thegroup consisting of chalk, talc, fullers earth, kaolin, starch, gums,colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammoniumsmectites, trialkyl aryl ammonium smectites, chemically modifiedmagnesium aluminum silicate, organically modified montmorillonite clay,hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodiumcarboxymethyl cellulose, ethylene glycol monostearate, and combinationsthereof.
 22. A mascara composition comprising: A) an active ingredientselected from the group consisting of a prostaglandin F analog havingthe structure

and pharmaceutically acceptable salts and hydrates of the prostaglandinF analog; biohydrolyzable amides, esters, and imides of theprostaglandin F analog; optical isomers, diastereomers, and enantiomersof the prostaglandin F analog; and combinations thereof; wherein R¹ isselected from the group consisting of CO₂H, C(O)NHOH, CO₂R⁵, CH₂OH,S(O)₂R⁵, C(O)NHR⁵, C(O)NHS(O)₂R⁵, and tetrazole; R² is selected from thegroup consisting of a hydrogen atom and a lower monovalent hydrocarbongroup; R³ and R⁴ are each independently selected from the groupconsisting of H, CH₃, C₂H₅, OR¹⁰, SR¹⁰, and OH; with the proviso thatboth R³ and R⁴ are not OH; R⁵ is selected from the group consisting ofmonovalent hydrocarbon groups, substituted monovalent hydrocarbongroups, aromatic groups, substituted aromatic groups, carbocyclicgroups, substituted carbocyclic groups, heterogeneous groups,substituted heterogeneous groups, heterocyclic groups, substitutedheterocyclic groups, heteroaromatic groups, and substitutedheteroaromatic groups; X is selected from the group consisting of NR⁶R⁷,OR⁸, SR⁹, S(O)R⁹, and S(O)₂R⁹; R⁶, R⁷, and R⁸ are each independentlyselected from the group consisting of hydrogen atoms, acyl groups,monovalent hydrocarbon groups, substituted monovalent hydrocarbongroups, heterogeneous groups, substituted heterogeneous groups,carbocyclic groups, substituted carbocyclic groups, aromatic groups,substituted aromatic groups, heteroaromatic groups, and substitutedheteroaromatic groups; R⁹ is selected from the group consisting ofmonovalent hydrocarbon groups, substituted monovalent hydrocarbongroups, heterogeneous groups, substituted heterogeneous groups,carbocyclic groups, substituted carbocyclic groups, heterocyclic groups,substituted heterocyclic groups, aromatic groups, substituted aromaticgroups, heteroaromatic groups, and substituted heteroaromatic groups;R¹⁰ is selected from the group consisting of a monovalent hydrocarbongroup, a substituted monovalent hydrocarbon group, a heterogeneousgroup, a substituted heterogeneous group, a carbocyclic group, asubstituted carbocyclic group, an aromatic group, a substituted aromaticgroup, a heteroaromatic group, and a substituted heteroaromatic group;with the proviso that R¹⁰ has 1 to 8 member atoms; Y is selected fromthe group consisting of an oxygen atom, a divalent hydrocarbon group, asulfur-containing moiety, and a nitrogen-containing group; and Z isselected from the group consisting of a carbocyclic group, a substitutedcarbocyclic group, a heterocyclic group, a substituted heterocyclicgroup, an aromatic group, a substituted aromatic group, a heteroaromaticgroup, and a substituted heteroaromatic group, dd) a water-insolublematerial, ee) a water-soluble, film-forming polymer, ff) a wax; o) asurfactant; gg) pigment; and s) a solvent.
 23. A method for darkeningand thickening hair comprising applying to growing hair and skin acomposition comprising: A) an active ingredient selected from the groupconsisting of a prostaglandin F analog having the structure

and pharmaceutically acceptable salts and hydrates of the prostaglandinF analog; biohydrolyzable amides, esters, and imides of theprostaglandin F analog; optical isomers, diastereomers, and enantiomersof the prostaglandin F analog; and combinations thereof; wherein R¹ isselected from the group consisting of CO₂H, C(O)NHOH, CO₂R⁵, CH₂OH,S(O)₂R⁵, C(O)NHR⁵, C(O)NHS(O)₂R⁵, and tetrazole; R² is selected from thegroup consisting of a hydrogen atom and a lower monovalent hydrocarbongroup; R³ and R⁴ are each independently selected from the groupconsisting of H, CH₃, C₂H₅, OR¹⁰, SR¹⁰, and OH; with the proviso thatboth R³ and R⁴ are not OH; R⁵ is selected from the group consisting ofmonovalent hydrocarbon groups, substituted monovalent hydrocarbongroups, aromatic groups, substituted aromatic groups, carbocyclicgroups, substituted carbocyclic groups, heterogeneous groups,substituted heterogeneous groups, heterocyclic groups, substitutedheterocyclic groups, heteroaromatic groups, and substitutedheteroaromatic groups; X is selected from the group consisting of NR⁶R⁷,OR⁸, SR⁹, S(O)R⁹, and S(O)₂R⁹; R⁶, R⁷, and R⁸ are each independentlyselected from the group consisting of hydrogen atoms, acyl groups,monovalent hydrocarbon groups, substituted monovalent hydrocarbongroups, heterogeneous groups, substituted heterogeneous groups,carbocyclic groups, substituted carbocyclic groups, aromatic groups,substituted aromatic groups, heteroaromatic groups, and substitutedheteroaromatic groups; R⁹ is selected from the group consisting ofmonovalent hydrocarbon groups, substituted monovalent hydrocarbongroups, heterogeneous groups, substituted heterogeneous groups,carbocyclic groups, substituted carbocyclic groups, heterocyclic groups,substituted heterocyclic groups, aromatic groups, substituted aromaticgroups, heteroaromatic groups, and substituted heteroaromatic groups;R¹⁰ is selected from the group consisting of a monovalent hydrocarbongroup, a substituted monovalent hydrocarbon group, a heterogeneousgroup, a substituted heterogeneous group, a carbocyclic group, asubstituted carbocyclic group, an aromatic group, a substituted aromaticgroup, a heteroaromatic group, and a substituted heteroaromatic group;with the proviso that R¹⁰ has 1 to 8 member atoms; Y is selected fromthe group consisting of an oxygen atom, a divalent hydrocarbon group, asulfur-containing moiety, and a nitrogen-containing group; and Z isselected from the group consisting of a carbocyclic group, a substitutedcarbocyclic group, a heterocyclic group, a substituted heterocyclicgroup, an aromatic group, a substituted aromatic group, a heteroaromaticgroup, and a substituted heteroaromatic group; and B) a carrier.